tbuckley/cabot-search huggingface dataset:
Abstract 958: Signal transduction pathway activity of TGF-β and Hedgehog as possible response predictors to checkpoint inhibition in patients with advanced melanoma; a retrospective cohort study
Authors: Stefan G. vanRavensteijn, Daniele V. Taurello, Avital Amir, Yvonne J. Wesseling, Anne G. vanBrussel, Diederick M. Keizer, Henk M. Verheul, Kalijn F. Bol
Journal: Cancer Research (2023)

Abstract Introduction: Although immunotherapy is highly effective in patients with melanoma, not all patients respond equally well to immune checkpoint inhibition (ICI). Preclinical data indicate that TGF-β pathway activity mediates immune evasion by tumor T cell exclusion and may therefore be predictive for response. Recently, a new mRNA-based methodology has been developed to measure and quantify signal transduction pathway (STP) activities in tissue. This study was initiated to characterize the STPs in advanced melanoma samples to better understand the role of STPs in immune check point efficacy. Method: The OncoSIGNal pathway activity profiling PCR test (InnoSIGN) was used to measure the activity of 8 different STPs (AR, PI3K, MAPK, Hedgehog (HH), TGF-β, Notch, NFkB and JAK-STAT1/2) in biopsies (FFPE) from patients with advanced melanoma (n=34) and expressed on a scale from 0 -100. A biopsy of a metastatic site was obtained prior start of ICI therapy (nivolumab or pembrolizumab). These samples were analyzed for STP activity and related to progression-free survival (PFS). Also, STP activities were compared between responders (n=15; partial or complete response) and non-responders (n=19; defined as progression within 6 months). Results: The mean HH score of responders versus non-responders was 35.7 + 6.1 vs 41.6 + 8.7 (p=0.038), while TGF-β scores were 53.9 + 6.2 vs 56.8 + 8.2 (p=0.265), respectively. Cox regression analysis showed a hazard ratio of 1-1.1 for PFS of both HH and TGF-β (HH: p=0.032) (TGF-β: p=0.071). Kaplan Meier curves indicated a better PFS for lower HH activity at a threshold of 46 (p&amp;lt; 0.001) and lower MAPK activity at a threshold of 47.3 (p= 0.041). No relation with PFS was detected for TGF-β activity. No statistically significant differences were observed in STP activity between different metastatic locations ((sub)cutaneous, lymph node or visceral metastases). Conclusion: Signal transduction pathway activity of metastatic samples, taken prior start of ICI therapy, from patients with advanced melanoma, suggest that TGF-β did not correlate with response nor PFS but increased HH and MAPK STP activity may relate towards a worse PFS from ICI therapy. Citation Format: Stefan G. vanRavensteijn, Daniele V. Taurello, Avital Amir, Yvonne J. Wesseling, Anne G. vanBrussel, Diederick M. Keizer, Henk M. Verheul, Kalijn F. Bol. Signal transduction pathway activity of TGF-β and Hedgehog as possible response predictors to checkpoint inhibition in patients with advanced melanoma; a retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 958.
Abstract 1160: A machine learning based method for in-vivo metabolic flux analysis of patient tumors
Authors: Anjali Mittal, Andrew Scott, Abhinav Achreja, Vijay Tarnal, Wajd Al-Holou, Costas Lyssiotis, Daniel Wahl, Deepak Nagrath
Journal: Cancer Research (2023)

Abstract Metabolic fluxes likely control cancer phenotypes and treatment responses but cannot be measured in cancers in human patients. Machine learning has become a popular tool to study cancer biology and can identify complex patterns in the data which may not be decipherable by traditional analyses. We propose an approach to combine 13C-tracer analysis with machine learning to quantify the metabolism of purines in glioblastoma patients. In recent years, multiple studies have been conducted on isotope tracing in cancer patients. While the data for the enrichment of metabolites in human tumors has improved our understanding of cancer metabolism, we lack methods to estimate metabolic fluxes from these enrichment values. A significant challenge in estimating the fluxes in human subjects is that we are limited to enrichment data from a single in-vivo measurement at isotopic non-steady state. We overcome this challenge by combining INST-MFA (Isotopic Non-Stationary-Metabolic Flux Analysis) with machine learning methods. We use the enrichment of circulating metabolites as an input and simulate the time-dependent metabolite enrichment profiles for randomized flux vectors. We use this data to train a convolutional neural network (CNN) model to predict the flux ratios. Apart from being able to predict the fluxes from a single time-point, a machine learning model drastically reduces the time required to fit a traditional INST-MFA model. We demonstrate the real-world validity of the model by predicting flux ratios in mice models and comparing them to results from traditional INST-MFA models. We apply the model to decipher the heterogeneity of the purine pathway in eight patients with brain tumors. Citation Format: Anjali Mittal, Andrew Scott, Abhinav Achreja, Vijay Tarnal, Wajd Al-Holou, Costas Lyssiotis, Daniel Wahl, Deepak Nagrath. A machine learning based method for in-vivo metabolic flux analysis of patient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1160.
Abstract 1684: Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis
Authors: Mi Jeong Kwon, Ha Yeong Chae, So Young Lee, Shin Ung Kang, Tae Woong Jung, Soo Youn Cho, Jinil Han, Hyojin Jeong, Chang Ohk Sung, Young Kee Shin
Journal: Cancer Research (2023)

Abstract Resistance to platinum-based chemotherapy is one of major causes of therapy failure and tumor recurrence in ovarian cancer patients. However, the molecular mechanism of platinum resistance is not fully understood. Here, we compared gene expression between cisplatin-sensitive and -resistant ovarian cancer cells using gene expression microarray analysis and found the significantly up-regulated expression of SERPINE1 encoding plasminogen activator inhibitor-1 (PAI-1), a serine protease regulating the fibrinolysis and extracelluar matrix, in cisplatin-resistant ovarian cancer cells. The correlation of high PAI-1 expression with low cisplatin sensitivity was confirmed in ovarian cancer cells. PAI-1 overexpression in ovarian cancer cells significantly decreased the sensitivity to cisplatin, whereas PAI-1 down-regulation by SERPINE1 siRNA or PAI-1 inhibitor increased cisplatin sensitivity. PAI-1 inhibited cisplatin-induced apoptosis in ovarian cancer cells by suppressing reactive oxygen species (ROS) production and DNA damage. PAI-1 also decreased cisplatin-induced ferroptosis through the upregulation of GPX4 levels. Furthermore, Kaplan-Meier survival analysis using TGGA data demonstrated that high PAI-1 expression was significantly associated with shorter platinum-free survival of patients with ovarian cancer. Collectively, these results illustrate that PAI-1 promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis, suggesting that targeting PAI-1 increases the sensitivity to cisplatin in ovarian cancer. Citation Format: Mi Jeong Kwon, Ha Yeong Chae, So Young Lee, Shin Ung Kang, Tae Woong Jung, Soo Youn Cho, Jinil Han, Hyojin Jeong, Chang Ohk Sung, Young Kee Shin. Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1684.
Abstract 2557: Targeting the IGF1R signaling pathway inhibits cell growth and dissemination in BCOR mutant retinoblastoma
Authors: Su-Chan Lee, Lujain Alaali, Charles G. Eberhart
Journal: Cancer Research (2023)

Abstract Retinoblastoma is the most common intraocular cancer of childhood, with approximately 8,000 new cases each year worldwide. While survival rates are relatively high in developed countries, death can occur in up to half of children in some regions. In addition, blindness is common in patients who survive, and improved therapies are clearly needed. While loss of RB gene function is essential for the initiation of almost all retinoblastoma, additional molecular changes driving their growth and dissemination are poorly understood. Improved understanding of the molecular pathways driving retinoblastoma growth and dissemination may allow us to develop more effective and less toxic therapies. Alterations leading to BCL-6 corepressor (BCOR) loss of function are the second most common mutations in retinoblastoma after changes affecting the RB locus, and are found in more aggressive tumors. BCOR mutations are also associated with metastasis and poor prognosis in other types of pediatric cancer, suggesting that targeting it will represent a new therapeutic approach for aggressive retinoblastoma. Here, we found that BCOR knockdown or knockout in two retinoblastoma cell lines with high baseline levels of protein caused significantly increased invasion/migration, proliferation and clonogenicity. In contrast, overexpression of BCOR in retinoblastoma cells with low/no baseline expression showed opposite effects. In orthotopic xenograft models, BCOR knockout dramatically increased the size and spread of retinoblastoma xenografts as compared to parental controls. In order to determine the molecular pathways modulated by BCOR, we used RNA sequencing and found that loss of function induces IGF1 transcription, resulting in activation of IGF1R and the ERK signaling pathway. Pharmacological inhibition of IGF1/IGF1R signaling using Lincitinib or AEW541 inhibited proliferation and migration in BCOR knockout retinoblastoma cells in vitro, and Lincitinib dramatically slowed xenograft growth in vivo, suggesting that induction of IGF1 represents an important downstream effector following BCOR loss. Our studies support a functional role for BCOR mutations in aggressive retinoblastoma, and suggest that this is mediated at least in part by increased IGF1R signaling, which represents a new therapeutic target for these malignant childhood tumors of the eye. Citation Format: Su-Chan Lee, Lujain Alaali, Charles G. Eberhart. Targeting the IGF1R signaling pathway inhibits cell growth and dissemination in BCOR mutant retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2557.
Abstract 3745: GRAS1 long non-coding RNA binds and stabilizes NF-kB activating protein to protect lung cancer cells from DNA damage
Authors: Tong Su, Bobby Kong, Jonathan Zhu, Colleen A. McHugh
Journal: Cancer Research (2023)

Abstract Long non-coding RNAs (lncRNAs) control numerous biological processes, including epigenetic regulation, gene expression, proliferation and metabolism. However, the detailed biological mechanisms by which lncRNAs regulate cellular processes are still poorly understood. We identified a set of growth regulator non-coding RNAs based on data mining of CRISPR/Cas9 screens and high-throughput sequencing studies from patient normal and tumor cells. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. In our screen, the Growth Regulator Antisense 1 RNA (GRAS1) was identified as a key factor controlling growth in non-small cell lung cancer cells. Loss of GRAS1 resulted in altered expression of genes involved in DNA repair, cell cycle progression, and p53 and NF-ΚB signaling pathways. Extensive DNA damage occurred within 48 hours after GRAS1 knockdown, with a significant increase in the number of γH2AX loci visualized by immunofluorescence assay. We used RNA antisense purification combined with mass spectrometry to identify the NF-ΚB activating protein (NKAP) as the top directly interacting partner of GRAS1 lncRNA. NKAP stability decreased after GRAS1 knockdown, and this phenotype could be reversed with proteasome inhibition. Further, RelA levels were decreased in GRAS1 knockdown cells. We found that GRAS1 lncRNA binds and stabilizes NKAP to enable survival and protect against DNA damage in lung cancer cells. Citation Format: Tong Su, Bobby Kong, Jonathan Zhu, Colleen A. McHugh. GRAS1 long non-coding RNA binds and stabilizes NF-kB activating protein to protect lung cancer cells from DNA damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3745.
Abstract 1648: Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors
Authors: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang
Journal: Cancer Research (2023)

Abstract PARP1/2 inhibitors are FDA approved for treatment of cancers such as ovarian, prostate, pancreas and breast with greatest activity against tumors harboring BRCA1 or 2 mutation or homologous recombination deficiency (HRD). A shared adverse event that contributes to a narrow therapeutic index and limits combination potential is hematologic toxicity. First generation PARP inhibitors are not selective against PARP2, which has been shown to play a role in the survival of hematopoietic progenitor cells in animal models. However genetic studies suggest that the synthetic lethality from PARP trapping with HRD is primarily dependent on PARP1. We hypothesized that a potent and selective PARP1 inhibitor and trapper would achieve equivalent anti-tumor activity as non-selective PARP inhibitors while alleviating toxicities caused by PARP2 inhibition. SNV-001 is a novel, proprietary, potent, and selective PARP1 inhibitor and trapper. In PARylation assays, SNV-001 inhibited PARP1 activity with low nanomolar potency and displayed greater than 500-fold selectivity against PARP2. In cellular PARP trapping assays, SNV-001 potently trapped PARP1 on DNA in a dose-dependent manner but did not trap PARP2 up to 25 µM. Functionally, SNV-001 exhibited selective growth inhibitory activity against cancer cell lines with impaired HR function. In anti-proliferation and colony formation assays of BRCA-mutant cell lines including MDA-MB-436 (BRCA1 deficient) and DLD1 (BRCA2 knockout), SNV-001 inhibited cell growth and colony formation with single-digit nM IC50 values while having minimal effects against BRCA-WT cells. In a subcutaneous MDA-MB-436 xenograft tumor model, SNV-001 administered orally once daily achieved dose-dependent inhibition of PARylation in vivo. Furthermore, SNV-001 showed dose-dependent tumor growth inhibition using low daily doses with greater efficacy compared to olaparib dosed at 100 mg/kg once daily. In the cohort receiving a higher dose of SNV-001, all animals showed complete regression after 35 days of treatment without any clinical signs of toxicity. In summary, we have discovered SNV-001, a potent and selective PARP1 inhibitor and trapper that shows excellent activity against cancer models with HRD in vitro and in vivo. These data support advancement of SNV-001 into clinical development for patients with tumors characterized by HRD. Citation Format: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang. Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1648.
Abstract 1967: Addressing breast cancer disparities: knowledge and attitudes towards cancer prevention through breastfeeding among African American women in Georgia
Authors: Marlo M. Vernon
Journal: Cancer Research (2023)

Abstract Background: A qualitative needs assessment was conducted to inform the development of a culturally competent breast and ovarian cancer prevention intervention, through the promotion of breastfeeding (BF) and genetic screening for cancer risk among African American (AA) women. In Georgia, AA women are diagnosed with later-stage breast/ovarian cancer and have higher mortality rates. BF initiation and longer duration are associated with reduced risk of cancers, yet BF rates are lower among AA women and few BF promotion programs are culturally competent. Methods: 20 AA Mothers (Age: 18-25y=40%, 25-29y=40%, 31-35y=20%; Edu: ≤HS=60%; # of children: 1=40%) who were either pregnant (n= 9, 45%) or within the first year postpartum (n= 11, 55%), were interviewed. Questions assessed BF intentions and prior experiences, knowledge of BF preventing cancer, familial breast/ovarian cancer risk, best promotion practices, and genetic screening attitudes. Results: Mothers (70%) reported previous BF initiation, with 65% reporting 6wks as the longest BF duration. No mother reported knowing that BF can prevent cancer. When asked about their own risk of cancer, a quarter of mothers reported knowing they were at risk of breast or ovarian cancer; a large majority (85%) were open to genetic screening and wanted to know their genetic risk for cancer. Mothers identified two themes: education and help/peer support to improve BF initiation and duration. There were no differences in responses based on demographics, BF experience, parity, or pregnancy/postpartum. Discussion: Results confirm a lack of knowledge of the cancer risk reduction conferred by BF. Women reported significant support for genetic screening and a need for education and peer social support for BF; these results will inform intergenerational cancer prevention education efforts. Citation Format: Marlo M. Vernon. Addressing breast cancer disparities: knowledge and attitudes towards cancer prevention through breastfeeding among African American women in Georgia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1967.
Abstract 2558: Loss of TC-PTP in keratinocytes leads to increased UVB-induced autophagy
Authors: Obed Asare, Klarissa Zavala, Lindsey Shim, Bilal Hafeez, Dae Kim
Journal: Cancer Research (2023)

Abstract Amongst the deteriorating effects of the sun’s ultraviolet B (UVB) radiation on cellular homeostasis is the formation of photoproducts in the DNA, such as cyclobutene pyrimidine dimers. Photoproducts cause conformational alterations in the DNA structure which may evade cellular repair machinery and persist through DNA replication processes, leading to potential gene mutations and ultimately leading to skin cancer. Photoproducts are typically repaired by nucleotide excision repair. Notwithstanding, when the repair mechanism fails, apoptosis ensues to prevent the accumulation of mutations and to restore cellular homeostasis. T-cell protein tyrosine phosphatase (TC-PTP) is one of the members of PTP family that has been shown to increase UVB-induced apoptosis in keratinocytes via the downregulation of Flk-1/JNK signaling. This implies that loss of TC-PTP causes resistance to apoptosis in UVB-damaged keratinocytes. In the present work, we report that this resistance is accompanied by an increase in UVB-induced autophagy in the absence of TC-PTP. We generated human TC-PTP-deficient (TC-PTP/KO) HaCaT keratinocytes using CRISPR/Cas9 system. The expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in TC-PTP/KO HaCaT keratinocytes compared to engineered controls (TC-PTP/Mock) following treatment with UVB irradiation. Increased expression of LC3 in TC-PTP/KO keratinocytes was accompanied by a significant decrease in the expression of the p62. We also observed that treatment of TC-PTP KO keratinocytes with chloroquine (CQ), a late-phase autophagy inhibitor, caused a remarkable increase in LC3 expression following UVB exposure in comparison with untreated TC-PTP/KO keratinocytes, implying that loss of TC-PTP increases autophagy in response to UVB. With this regard, TC-PTP deficiency in human keratinocytes significantly increased cell proliferation following UVB exposure compared to similarly treated control keratinocytes. Pretreatment of CQ before UVB irradiation in TC-PTP KO keratinocytes significantly reduced cell viability compared to untreated TC-PTP KO keratinocytes. These results suggest that TC-PTP protects keratinocytes from UVB-induced damage by negatively regulating autophagy signaling. Citation Format: Obed Asare, Klarissa Zavala, Lindsey Shim, Bilal Hafeez, Dae Kim. Loss of TC-PTP in keratinocytes leads to increased UVB-induced autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2558.